Diol dione compounds and method of making same

ABSTRACT

A process for the preparation of dioldione compounds of the formula   BY OZONIZING AN REDUCING A COMPOUND OF THE FORMULA

United States Patent Re et a]. Apr. 17, 1973 DIOL DIONE COMPOUNDS AND [56] References Cited TH D F M N AME ME 0 0 AK} G S UNITED STATES PATENTS [75] Inventors: Luciano Re, Meyrin/Geneva; 2 175 58 0/1939 V h 260/593 R Gfinther ohloff, Bemx/Geneva, z ug both of Switzerland 2,789,141 4/1957 Fnedench et a] ..260/593 R [73] Assignee: Firmenich & Cie, Geneva, Switzer- OTHER PUBLICATIONS a Re et al., Chem. Abs. 72, 42,809n 1970). [22] Filed: Dec- 12, 1969 Re et al., Chem. Ales. 72, 31,5985 (1970). [2]] App]. N0.: 889,811 Primary Examiner-Daniel D. l-lorwitz AttorneyPennie, Edmond, Morton and Adams Related US. Application Data {62] Division of Ser. No. 736,269, June 12, 1968, Pat. No. [57] ABSTRACT 3,576,014" A process for the preparation of dioldione compounds of the formula [30} Forelgn Application Priomy Data curmkc June 16, 1967 Switzerland ..8620/67 ll ()II June 5, 1968 Switzerland ..8254/68 y ozonizing an reducing a compound of the formula [52] US. CL...T ..260/594 7 (7,][; C]I C EC C]I C]{3 I [51] Int. Cl ..C07c 49/12 H H [58] Field of Search ..260/594 R, 593R 4 Claims, No Drawings DIAL DIONE COMPOUNDS AND METHOD OF MAKING SAME This application is a division of our application Ser. No. 736,269, filed June 12, 1968, now issued as U. S. Pat. No. 3,576,014.

The present invention relates to a novel process for preparing dihydrofuran derivatives of formula OT,- OH L. I

wherein one of the symbols R means a methyl radical and the other one an ethyl radical or wherein both symbols R represent methyl radicals. The compounds of formula I possess valuable organoleptic properties and are, therefore, useful as flavouring agents and as fragrances. The invention also relates to those compounds of formula I wherein one of the Rs is ethyl and which are new substances. The invention furthermore relates to new intermediates used in the said new process and to methods for preparing them.

A known method for preparing 2,5-dimethyl-4,5- dihydro-furan-3-ol-4-one (formula I, both Rs methyl) consists in heating rhamnose in the presence of piperidine acetate (cf. Proc. Am. Soc. Brewing Chemists 84 (1963)). The starting rhamnose is a relatively expensive natural product which can be obtained only in small insufficient quantities and which, therefore, is not a suitable starting material for the commercial production of the said dihydrofuran derivative.

Another known method for preparing 2,5-dimethyl- 4,5-dihydrofuran-3-ol-4-one comprises hydrogenolising acetylformoin by treating the latter with hydrogen in the presence of a palladium-carbon-catalyst and pu-- .rifying the crude product by chromatography on silica (cf. Helv. Chim. Acta 49, 53 (1966)). The yield of pure product is only about 10 percent of thetheory.

A further known method for preparing 2,5-dimethyl- 4,5-dihydrofuran-3-ol- 4-one consists in catalytically hydrogenating 2,5-dihydroxymethyl-3,4-dibenzoxyfuran (cf. J.Org.Chem. 31, 2,391 (1966)). The main disadvantage of this method resides in the fact that the synthesis of the intermediate 2,5-dihydroxymethyl- 3,4-dibenzofuran requires four chemical steps. Furthermore, the overall yield of the desired product amounts to about 6.5 percent of the theory only.

The known methods described above are noneconomical laboratory methods'which cannot be applied to the production of the said dihydrofuran derivative on a commercial scale. It has now been found that the compounds of formula I can be obtained easily and economically from new intermediates which are derived from cheap starting materials available commercially in unlimited quantities.

The process according to the invention comprises cyclising, in the presence of a cyclisation catalyst, a diol-dione compound of formula II II (II) wherein R represents an ethyl or a methyl radical.

For the cyclisation which proceeds with elimination of one molecule of water, cyclisation catalysts such as proton donors for instance mineral or organic acids can be used. These include hydrochloric acid, sulphuric acid, phosphoric acid, oxalic acid, acetic acid, malonic acid, tartaric acid, trifluoroacetic acid and acid buffers resulting from acidic mixtures of said acids and alkali or amine salts thereof for instance acid buffers such as mixtures of phosphoric acid and sodium or ammonium phosphate, mixtures of sulphuric acid and potassium sulphate, mixtures of hydrochloric acid and ammonium chloride or acetic acid and piperidine acetate or oxalic acid and triethylamine oxalate or trifluoracetic acid and pyridine trifluoracetate. Preferred cyclisation catalysts are hydrochloric and oxalic acids.

The removal of the water eliminated during the cyclisation from the cyclisation mixture is not necessary for obtaining a good yield of cyclised product. The

cyclisation can be performed in aqueous solutions, for instance mixtures, of water and hydrophilic solvents such as methanol, ethanol, dioxan, tetr'ahydrofuran and dimethoxyethane. A preferred class of solvents includes pure water, methanol-water or ethanol-water mixtures. According to the mass action laws it was to be expected that the presence of water would inhibit the cyclisation. However, not only the water formed during the cyclisation but also the additional water present in the reaction medium have no detrimental effect on the course of the cyclisation.

The cyclisation can be carried out at temperatures comprised between 50 and 150 C, preferably at the reflux temperature of the reaction mixture, under an inert atmosphere for instance nitrogen or C0,.

The compounds of formula II are new and can be obtained according to the invention by ozonation of the corresponding acetylenic diols of formula OH OH (III) wherein R is an ethyl or methyl radical, and subsequent reduction of the intermediate ozonide by means of a reducing agent. The ozonation can be perfonned according tousual ozonation procedures for instance by bubbling into a solution of the acetylenic compound gaseous mixtures of 1 to 5 percent ozone in oxygen at The ozonation can be carried out in the presence of polar organic solvents such as acetone, methanol, ethanol or isopropanol, or organic acids such as acetic, formic and propionic acids. Low boiling alcohols such as methanol or ethanol. and acetic acid are a'preferred class of solvents for the ozonation since they also stabilise the intermediate ozonide by formation of alkoxyhydroperoxides and acetoxyhydroperoxides, respectively.

The intermediate ozonide can be reduced to the dioldione by using agents such as alkali iodides, e.g. lithium, potassium or sodium iodides, organic sulphides, e.g. methyl, ethyl, propyl or butyl sulphides or an arcmatic or aliphatic tertiary phosphine for instance triphenylphosphine, tritolylphosphine, tributylphos phine, trihexylphosphine. Triphenylphosphine is a preferred reducing agent.

The process according to the invention offers several advantages over the prior art methods for preparing 2,5-dimethyl-4,S-dihydrofuran-B-ol-4-one with regard to yields, cost of manufacture and availability of starting materials. i I

2-Methyl-5-ethyl-4,5-dihydrofuran-3-ol-4-one (isomer A) and methyl-2-ethyl-4,5-dihydrofuran-3- ol-4-one (isomer B), which are both new compounds, are obtained when heptane- 2,5-diol-3,4-dione is used as the startingcompound in the process according to the invention. A and B are obtained as a mixture in proportions byv weight of about 2 1. They can be separated for instance by molecular distillation in vaccuo at bath temperatures not exceeding 50 C. or by counter-current extraction. Both isomers have interesting organoleptic properties and are, therefore, useful as flavouring agents, in particular for flavouring foodstuffs, beverages and pharmaceutical preparations.

III(R =methyl) Furthermore, they can be used as ingredients in artificial flavours, especially fruit flavours such as raspberry,

I strawberry, gooseberry flavours and the like. lsomers A andB are also useful as reinforcing agents for improving or strenghtening the flavours of fruit juices, fruit pulps, jams and canned fruit. As distinct from 2,5- dimethyl-4,5-dihydrofuran-3-ol-4-one which developps a characteristic strawberry-like flavour the saidisomers A and B have different flavouring properties insofar as they develop a weaker and non-specific fruity flavour note but. a strong cooked flavour note. Thus, e.g., if minute quantities of a mixture of isomers A and B is added toa natural raspberry syrup a flavour note of cooked raspberry is imparted to the syrup. The same effect is obtained in various other fruit flavours. isomers A and B are particularly useful for enhancing the flavour and taste of various fruit jams and canned fruit.

The quantities of isomers A and/or B which have to be used in order to produce the desired flavouring effects vary within wide limits according to the nature of the material to be flavoured. As an average, good results are obtained in modifying or enhancing the flavour and taste of, foodstuffs, e.g. fruit jams, and beverages with proportions of 5 to 15 mg. of isomers A and/or B for one kilogram of foodstuff or beverage. However, these figures should not be construed as limitations. Higher or lower proportions can be used depending on the desired flavour effects.

For practical flavouring purposes it is not necessary to separate'the two isomers since their flavouring properties are substantially identical. Thus, a mixture of both isomers as it is obtained in the cyclisation of heptane-2,5-diol-3,4-dione according to the invention can be used as aflavour-modifying agent.

Surprisingly, the flavouring strength of 2-methy1-5- ing strength. Thus, for instance, the flavouring strength of S-methyl-furfural is from 5 to 10 times lower than that of furfural.

The invention and its embodiments are further illustrated by the following Examples.

EXAMPLE 1 Preparation of 5-methyl-2-ethyl-4,5-dihydrofuran-3- ol-4-one and 2-methyl-5-ethyl-4,5-dihydrofuran-3-ol- 4-one a. 3-heptyne-2,5-diol To a stirred suspension of magnesium turnings (48.6 g.) in ether (500 ml.), a solution of ethyl bromide (153 ml.) in ether (180 ml.) was added dropwise in the course of 4% hours at such a rate that the heat of-reaction would maintain the mixture at reflux temperature. During this period the reflux condenser was kept at -10 C in order to prevent escaping of the ethyl bromide. I

The reaction mixture was cooled and a solution of lbutyne-3-o1 (70.1 g.) in ether (90 ml.) was added dropwise between O and 5 in the course of 3% hours..This resulted in a pasty mass which was resuspended by the addition of 500 ml. of benzene. The mixture was stirred for 2 hours at. 47-50 (bath-temperature) then cooled down to 5 C. Then a solution of proprionaldehyde (63.9 g., 79 ml.) in benzene (80ml) was added dropwise with stirring during a period of 20 minutes. The mixture was stirred overnight at room temperature then poured slowly into a saturated ammonium chloride solution 2 1.), keeping the temperature below 15 C.-by means of external cooling.'The pH of the mixture was adjusted to a value of 6 by the dropwise additionof concentrated HCl, then theorganiclayer was separated and the aqueous layer evaporated to dryness under vacuum at a temperature below 60 C. The residue was extracted several times with chloroform and the combined extracts, after having beendried over anhydrous Na,SO were concentrated under vacuum. The resulting brown oil (118 g.) was flashdistilled and gave 106 g. of 3-heptyne-2,5-diol having a b.p. of 8383.5/0.1 Torr and a purity of 94 percent according to vapour phase chromatography analyses. Yield 77 percent.

b. Heptane-2,5-diol-3,4-dione A gaseous stream containing 4.5 g. of 0, per 1001. of O, was introduced at the rate of l. of gas/hour into a solution of 128 g. of 3-heptyne-2,5-diol in 1.3 l. of methanol cooled to l0 C. After about 10 hours the extent of ozone consumption in the reaction mixture was checked by means of the usual sodium iodide-sodium thiosulphate test and shown to be about 90 percent of the theory. The ozonation was stopped and into the mixture cooled between 20 and 30 C. a solution of triphenylphosphine (262 g.) in ether (1.2 l.) was added dropwise with stirring. During this period the temperature was kept below 0 C. The volatile solvents were removed under vacuum and in order to separate the product from the triphenylphosphine oxide, the residue was extracted carefully with water warmed to 50 C. (3 portions of 1 1. each). The combined water extracts were usually used directly in the following cyclisation step (see paragraph c) below. For the isolation of the diodione the above water extracts were shaken with ethyl acetate and the organic layer was separated, dried and concentrated under vacuum (bath temperature 35 C.). A pale yellow solid (yield 75 percent) was thus obtained, the purity of which was 80 percent or better according to the vapour phase chromatography analyses. When desired, the substance could be redissolved in water and cyclised according to the procedure described below.

c. Cyclisation of heptane-2,5-diol-3,4-dione The combined water extracts separated from the residual phosphine oxide according to b) above were concentrated under vacuum until the total volume of the solution was reduced to about 1.5 l. Oxalic acid dihydrate (60 g.) was added and the solution heated to the boil under nitrogen for 6 hours. After cooling, the solution was brought to pH 6-6.5 by means of a 20 percent KOH solution then it was continuously extracted for 40 hours with ether (1 l.). The ether extract was dried and after being vacuum-distilled gave a 2 1 mixture of 2-methyl-5-ethyl-4,5-dihydrofuran-3-ol-4-one (A) and 5-methyl-2-ethyl-4,5-dihydrofuran-3-ol-4-one (B), yield 70percent, b.p. 6366 C./0.0l5 Torr. The above mixture was used directly to flavour foods and beverages.

The mass spectrum of the above mixture gave the following main results: m/e 142 (66), 99 (18), 71 (42), 57 (97), 43 (100). isomers A and B were isolated by counter-current solvent partition extraction using water as the heavy phase and a mixture of pentane and hexane as the light phase. They gave the following characteristic NMR data.

groups H resonance 8 ppm 8 Methyl (isolated) 2.23, s l.4l,d ,]=cps Methyl (from ethyl radical) 0.97,t,J=cps l.24,t,J=cps Methylene (from ethyl radical) Z.61,q,.!=cps Hydroxy 7.1 7.1

EXAMPLE 2 Preparation of 2,5-dimethyl-4,5-dihydrofuran-3-ol- 4-one a. Hexane-2,5-diol-3,4-dione A gaseous stream containing 4.5 g. of 0 per 300]. of O, was bubbled at the rate of 901. of gas/hour in a solution of 1 14 g. of sym-hexyne-2,5-diol in 1.3 l. of methanol cooled to C. After about 10 hours the extent of ozone consumption in the reaction mixture was checked by means of the usual sodium iodide-sodium thiosulphate test and shown to be about 90 percent of the theory. The ozonation was stopped and into the mixture cooled between and -30 C a solution of triphenylphosphine (262 g.) in ether (1.2 l.) was added with stirring. During the reduction the temperature was maintained below 0 C. The volatile solvents were removed under vacuum and in order to separate the product from the residual triphenylphosphine oxide, the residue was extracted twice with water (1 liter fractions). The combined water extracts were shaken with ethyl acetate and the organic layer was separated, dried and concentrated under vacuum. 146 g. of crude hexane-2,5-diol-3,4-dione, percent pure according to vapour phase chromatography analysis, and corresponding to g. of pure product were thus obtained. Yield 75 percent. This product could be used directly for the cyclisation reaction without further purification (see paragraph b) below).

b. Cyclisation of hexane-2,5-diol-3,4-dione Crude hexane-2,5-diol-3,4-dione (50 g.) and oxalic acid dihydrate (20 g.) was dissolved in 500 ml. of water. The solution was heated to the boil for 4 hours under nitrogen. After cooling the pH of the solution was adjusted to a value of 6-6.5 by the addition of 20 percent KOH solution. The solutionwas filtered and continuously extracted for 40 hours with 300 ml. of ether. The ether was removed from the extract under vacuum and the residue was purified bu sublimation (bath temperature 70-80, pressure 0.01 Torr) and gave a 75 percent yield of pure 2,5-dimethyl-4,5- dihydrofuran-3-ol-4-one, m.p. 7779.

EXAMPLE 3 temperature below 35 C). By distilling the residue under a pressure of 0.05 Torr, dimethylsulphoxide was eliminated. The product remaining in the distillation vessel was diluted with chloroform, filtered and again concentrated under vacuum. This gave crude hexane- 2,5-diol-3,4-dio ne which could be cyclised without further purification by the method described in Example 2.

EXAMPLE 4 Cyclisation of hexane-2,5 -diol-3,4-dione.

A solution of 15.5 g. of hexane-2,5-diol-3,4-dione, prepared according to Example 3, 1 ml. of HCl in ml. of water was heated to the boil for 6 hours under nitrogen. After neutralisation with 5 percent KOH solution, the mixture was treated as described in Example 2, paragraph b) and gave 2.9 g. of pure 2,5-dimethyl- 4,5-dihydrofuran-3-ol-4-one, m.p. 7779 C.

The following Examples illustrate the use of 2- methyl-S-ethyl-4,5-dihydrofuran-3-ol-4-one (isomer A) and 2-ethyl-5-methyl-4,5-dihydrofuran-3-ol-4-one (isomer B) as flavouring agents.

EXAMPLES A raspberry syrup was prepared by diluting 5 g. of a natural raspberry concentrate with 1 liter of 30 percent aqueous sugar solution. The resulting syrup was devided into two equal portions. To one of these portions 5 mg. of an additive consisting of a mixture of isomers A and B (ratio by weight about 2 l) was added. The

I ditive had a distinct cooked raspberry flavour note as compared with the control syrup having a more fresh raspberry flavour and taste.

The same experiment was carried out using a natural strawberry-concentrate. Again, the syrup portion containing the additive was found to have a cooked raspberry flavour note which was not present in the control syrup.

EXAMPLE 6 An artificial green gooseberry flavour was prepared by mixing the following ingredients:

Ingredients Parts by weight Vanillin 0.20 Ethyl caproate 0.50 Allyl caproate 0.50 lsobutyl caproate 0.50 Ethyl pelargonate 0.50 lsovalerianic aldehyde 0.05 Methyl-phenyl-carbinyl acetate 0.05 Anisalcohol 0.20 Raspberry ketone 0.20 Ethyl benzoate 0.20 Methyl-phenyl-carbinfl isobutyrate 0. l Geraniol 0.20 Green cognac oil 0.20 Ethyl butyrate 2.00 Ethyl acetate 2.00 Triacetine 2.60

' Total: 10.00

divided into two equal portions. To one of these portions 10 mg. of an additive consisting of a mixture of isomers A and B (ratio by weight about 2 l) was added. The other syrup portion was used as a control for comparison purposes. Both syrups were tasted by several persons which agreed that the syrup containing.

H OH (II) wherein R represents a methyl or ethyl radical.

2. Hexane-2,5-diol-3,4-dione.

3. Heptane-2,5-diol-3,4-dione.

4. A process for the preparation of diol dione compounds of the formula wherein R represents a methyl or ethyl radical which comprises treating acetylenic diols, of formula cm-cn-cz c clr n wherein R represents a methyl or ethyl radical, with an ozonizing agent comprising ozone in a polar solvent and at a temperature below 0 C for a time sufficient to form the corresponding ozonide, and reducing the resulting ozonide to the corresponding diol-dione by means of a reducing agent selected alkali iodides, organic sulphides, and aromatic or aliphatic tertiary phosphines.

UNITED STATES PATENT OFFICE I CERTIFICATE OF CORRECTION Patent No. 3, 728 397 Dated 'April 17 19 73 Inventor(s) 'Luclano 6 8t a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

The abstract should read:

A process for the preparation of diol dione compounds of the formula CH3CH-CO-CO-CH-R on H wherein R represents a methyl or ethyl radical which comprises ozonizing acetylenic diols, of formula CH -CH- CEC-CH-R wherein R represents a methyl or ethyl radical.

Signed-and sealed this 20th day of August 1974.

(SEAL) Attest:

McCOY M. GIBSON, JR. 7 C. MARSHALL DANN Attesting Officer Commissioner of Patents FORM Po-10s0 uo-ss) uscoMM-Dco037e-P69 Q lLS. GOVERNMENT PRINTING OFFICE I969 0-366-334,

UNITED STATES PATENT orrrea CERTIFICATE OF CQRRECTWN Patent No. 3,728,397 Dated April 17, 1973 Inventor(s) Luclano Re et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 13, "eliminated" should read formed Column 3, line 17, "(R=methyl)" should read (R=ethyl) Column 5, line 43, "l.4l,d,J=cps" should read l.4l,d,J=7cps line 44, "0.97,t,J=cps" should read 0.97,t,J=7cps line 44, "l.24,t,J=cps" should read 1.Z4,t,J=7cps line 45, "2.,6l,q,J=cps" should read 2.6l,q,J=7.5cps line 53,

"per 300 1." should read per 100 l. Column 6, .line 20, "by" should read by line 35, O, should read Signed and sealed this 19th day of February 1974.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents FORM Po-1050 (10.69) US COMM'DC BO376-P69 U.S. GOVERNMENT PRINTING OFFICE I959 0-365-334. 

2. Hexane-2,5-diol-3,4-dione.
 3. Heptane-2,5-diol-3,4-dione.
 4. A process for the preparation of diol dione compounds of the formula 